Abstract 15259: Ventricular Dysfunction and Blunted Response to Adrenergic Stimulation in Obese Type 2 Diabetes Predispose to Fatal Heart Failure After Infarction: Possible Involvement of MicroRNA-1 Down-Regulation
Background: We recently reported that cardioprotective signaling is disrupted in obese type 2 diabetes (T2DM) by up-regulation of calcineurin. A recent study has indicated that microRNA-1 (miR-1) modulates phosphorylation of L-type Ca2+ channels via regulation of protein phosphatase 2A (PP2A). Here we assessed alterations in ventricular functions and outcomes after myocardial infarction in light of changes in calcineurin activity and expression of miRs.
Methods and Results: Using TaqMan® MicroRNA Array v2.0 (Applied Biosystems), we compared myocardial expression levels of 595 verified miRs between OLETF, a rat model of obese T2DM, and LETO, non-diabetic controls. We found that 21 miRs were up-regulated and 31 miRs, including miR-1, were down-regulated in OLETF. Although left ventricular ejection fraction (LVEF) was comparable between OLETF and LETO (55.5±4.4 vs. 59.9±6.0%), heart rate (292.2±8.1 vs. 362.4±11.3 bpm), left ventricular end-systolic elastance (1.68±0.10 vs. 1.95±0.08 mmHg/μl) and LV dP/dtmax (5886±413 vs. 7839±560 mmHg/s) were slightly lower and tau was larger (12.1±1.15 vs. 8.87±0.96 msec) in OLETF than in LETO. Increase in LV dP/dtmax by dobutamine challenge (5∼20 μg/kg, i.v.) was lower by ∼30% in OLETF than in LETO, and the inhibitory effect of verapamil on LV dP/dtmax response to dobutamine was blunted in OLETF. Using separate groups of rats, infarction was induced by coronary ligation. Before ischemia, LVEF and %FS determined by echocardiography were similar in OLETF and LETO. However, mortality 48 hrs after infarction was significantly higher in OLETF than in LETO (58.4% vs. 7.7%), and telemetric recording indicated that rapid progression of heart failure, but not ventricular arrhythmias, was responsible for the higher mortality in OLETF. Pretreatment with cyclosporin A, a calcineurin inhibitor, did not reduce the mortality in OLETF.
Conclusion: The findings support the notion that down-regulation of miR-1 contributes to ventricular systolic/diastolic dysfunction and blunted response to adrenergic stimulation by reduction of phosphorylation of L-type Ca2+ channels, predisposing to high mortality after infarction, in T2DM.
- © 2010 by American Heart Association, Inc.